Abstract

Polycystic ovary syndrome (PCOS) affects reproductive‐aged women, manifesting reproductive and hyperandrogenic features and
associated cardio‐metabolic risk factors that include increased risk for development of type 2 diabetes. Twin‐based studies
have confirmed a heritability of ∼70% for PCOS, with likely oligogenic predisposition, its clinical and biochemical abnormalities
often highlighted by weight gain. Much current literature on PCOS genetics is based on a candidate gene approach, with controversial
and conflicting results from reporting of almost universally under‐powered studies. In recent years, this approach has been
superseded by the Genome‐Wide Association Study (GWAS) with its advantage of encompassing the entire genome without any need
for a priori understanding of pathophysiology. Reported GWAS in PCOS from both Chinese and European ancestry have revealed novel insight
that implicate genetic variants influencing secretion and action of gonadotrophins in susceptibility for development of this
condition. Epigenetic factors probably also play an important role in the heritability of PCOS.

Key Concepts

PCOS is an oligogenic condition with a heritability of ∼70%.

PCOS is characterised by reproductive and hyperandrogenic features.

Genetics studies in PCOS are limited by the heterogeneity of the condition, the inherent reduced fertility and difficulty
with accurate retrospective diagnosis in postmenopausal women.

Existing candidate gene studies implicate variants within FTO (through effects on fat mass) and variants that influence steroidogenesis (such as 5α‐reductase activity) in possible susceptibility
for development of PCOS.

Genome‐wide association studies (GWASs) on Chinese and European populations have identified loci that implicate gonadotrophin
secretion (including FSHB) in susceptibility for development of PCOS.

Loci identified from GWAS in PCOS only account for a small proportion of the overall heritability of PCOS. Rarer, yet to be
identified, genetic variants with large effects may yet play a part but it is also likely that other factors, such as epigenetics,
may contribute to the remainder of this known heritability.

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